Impact of atrial fibrillation on outcomes in asymptomatic severe aortic stenosis: a propensity-matched analysis.

Background: Atrial fibrillation (AF) portends poor prognosis in patients with aortic stenosis (AS). Objectives: This study aimed to study the association of AF vs. sinus rhythm (SR) with outcomes in asymptomatic severe AS during routine clinical practice. Methods: We identified 909 asymptomatic patients from 3,208 consecutive patients with aortic valve area ≤1.0 cm2 and left ventricular ejection fraction ≥50% at a tertiary academic center. Patients were grouped by rhythm at the time of transthoracic echocardiogram [SR: 820/909 (90%) and AF: 89/909 (10%)]. Propensity-matched analyses (2 SR:1 AF) matching 174 SR to 89 AF patients by age, sex, and clinical comorbidities were used to compare outcomes. Results: In the propensity-matched cohort, median age (82 ± 8 vs. 81 ± 9 years, p = 0.31), sex distribution (male 58% vs. 52%, p = 0.30), and Charlson comorbidity index (4.0 vs. 3.0, p = 0.26) were not different in AF vs. SR. Median follow-up duration was 2.6 (IQR: 1.0-4.4) years. The 1-year rate of aortic valve replacement (AVR) was not different (AF: 32% vs. SR: 37%, p = 0.31). All-cause mortality was higher in AF [hazard ratio (HR): 1.68 (1.13-2.50), p = 0.009]. Independent predictors of mortality were age [HR: 1.92 (1.40-2.62), p < 0.001], Charlson comorbidity index [1.09 (1.03-1.15), p = 0.002], aortic valve peak velocity [HR: 1.87 (1.20-2.94), p = 0.006], stroke volume index [HR: 0.75 (0.60-0.93), p = 0.01], moderate or more mitral regurgitation [HR: 2.97 (1.43-6.19), p = 0.004], right ventricular systolic dysfunction [HR: 2.39 (1.29-4.43), p = 0.006], and time-dependent AVR [HR: 0.36 (0.19-0.65), p = 0.0008]. There was no significant interaction of AVR and rhythm (p = 0.57). Conclusions: Lower forward flow, right ventricular systolic dysfunction, and mitral regurgitation identified increased risk of subsequent mortality in asymptomatic patients with AF and AS. Additional studies of risk stratification of asymptomatic AS in AF vs. SR are needed.

Impact of Atrial Fibrillation on Outcomes in Very Severe Aortic Valve Stenosis.

The prevalence and impact of atrial fibrillation (AF) versus sinus rhythm (SR) on outcomes in very severe aortic stenosis (vsAS) of the native valve is unknown. The aim of the study was to determine the prognostic significance of AF in vsAS. A total of 563 patients with vsAS (transaortic valve peak velocity ≥5 m/s) and left ventricular ejection fraction ≥50% were identified retrospectively. Patients were divided by rhythm at the time of index transthoracic echocardiogram (AF: n = 50 [9%] vs SR: n = 513 [91%]). Patients with AF were older (83.1 ± 7.5 vs 72.5 ± 12.2 y, p <0.001) and had no difference in gender distribution (p = 0.49) but had a higher Charlson co-morbidity index (2 [1,3] vs 1 [0,2], p = 0.01). There was no difference in transaortic peak velocity (5.3 ± 0.3 m/s vs 5.4 ± 0.4 m/s, p = 0.13) and left ventricular ejection fraction was comparable (63 ± 7 vs 66 ± 7%, p = 0.01). Age-, gender-, Charlson co-morbidity index-, and time-dependent aortic valve replacement (AVR)-adjusted overall mortality at 5 years was significantly higher in patients with AF than patients with SR (hazard ratio [HR] 1.88 [1.23 to 2.85], p = 0.003). AVR was associated with improved survival (HR = 0.30 [0.22 to 0.42], p <0.001), with no statistically significant interaction of AVR and rhythm (p = 0.36). Outcomes were also compared in the 2 SR:1 AF propensity-matched analyses (100 SR: 50 AF), with matching done according to age, gender, clinical co-morbidities, and year of echocardiogram. In the propensity-matched analysis, age-, gender-, and time-dependent AVR-adjusted all-cause mortality was higher in AF (HR 2.32 [1.41 to 3.82], p <0.001). In conclusion, AF was not uncommon in vsAS and identified a subset of patients at a much higher risk of mortality without AVR.

What are the minimum requirements to establish proficiency in lung ultrasound training for quantifying B-lines?

AIMS: The goal of this study was to determine the number of scans needed for novice learners to attain proficiency in B-line quantification compared with expert interpretation. METHODS AND RESULTS: This was a prospective, multicentre observational study of novice learners, physicians and non-physicians from three academic institutions. Learners received a 2 h lung ultrasound (LUS) training session on B-line assessment, including lecture, video review to practice counting and hands-on patient scanning. Learners quantified B-lines using an eight-zone scanning protocol in patients with suspected acute heart failure. Ultrasound (US) machine settings were standardized to a depth of 18 cm and clip length of 6 s, and tissue harmonics and multibeam former were deactivated. For quantification, the intercostal space with the greatest number of B-lines within each zone was used for scoring. Each zone was given a score of 0-20 based on the maximum number of B-lines counted during one respiratory cycle. The B-line score was determined by multiplying the percentage of the intercostal space filled with B-lines by 20. We compared learner B-line counts with a blinded expert reviewer (five US fellowship-trained faculty with > 5 years of clinical experience) for each lung zone scanned; proficiency was defined as an intraclass correlation of > 0.7. Learning curves for each learner were constructed using cumulative sum method for statistical analysis. The Wilcoxon rank-sum test was used to compare the number of scans required to reach proficiency between different learner types. Twenty-nine learners (21 research associates, 5 residents and 3 non-US-trained emergency medicine faculty) scanned 2629 lung zones with acute pulmonary oedema. After a mean of 10.8 (standard deviation 14.0) LUS zones scanned, learners reached the predefined proficiency standard. The number of scanned zones required to reach proficiency was not significantly different between physicians and non-physicians (P = 0.26), learners with no prior US experience vs. > 25 prior patient scans (P = 0.64) and no prior vs. some prior LUS experience (P = 0.59). The overall intraclass correlation for agreement between learners and experts was 0.74 and 0.80 between experts. CONCLUSIONS: Our results show that after a short, structured training, novice learners are able to achieve proficiency for quantifying B-lines on LUS after scanning 11 zones. These findings support the use of LUS for B-line quantification by non-physicians in clinical and research applications.

Spectrum of KV 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

OBJECTIVE: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. METHODS: We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant KV 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. RESULTS: Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type KV 2.1. Quantification of protein expression also identified variants with reduced total KV 2.1 expression or deficient cell-surface expression. INTERPRETATION: Our study establishes a platform for rapid screening of KV 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.

BACKGROUND: The explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that have implications for diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels as in congenital arrhythmia syndromes, in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost, time, and labor intensive. METHODS: We implemented a strategy for performing high-throughput functional evaluations of ion channel variants that repurposed an automated electrophysiological recording platform developed previously for drug discovery. RESULTS: We demonstrated the success of this approach by evaluating 78 variants in KCNQ1, a major gene involved in genetic disorders of cardiac arrhythmia susceptibility. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. This strategy also enabled studies of dominant-negative behavior of variants exhibiting severe loss-of-function. Overall, our results provided functional data useful for reclassifying >65% of the studied KCNQ1 variants. CONCLUSIONS: Our results illustrate an efficient and high-throughput paradigm linking genotype to function for a human cardiac ion channel that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.